Gastric immune responses interact with bacterial virulence factors to promote the pathogenesis of diseases associated with H. pylori infection. While helper T (Th) cells promote inflammation in response to H. pylori in both humans and mice, they are also essential for immunity in animal models. Effective immunity can be induced by vaccination although antibody responses are not necessary. Since/-/. pylori is a noninvasive pathogen, the "protective" Th cells are believed to modify epithelial cell gone expression such that the niche favoring colonization is disrupted. Th1 cells can augment expression of receptors that bind H. pylori and favor the epithelial damage that ensues. As such, they act as a "pathogenic" T cell. Either endogenous or exogenous ROS can regulate the expression of genes associated with Th1 cells. In contrast, Th2 cells, through the production ofIL-4, IL-5, IL-10, IL-13, IL-25 and TGF-Beta can antagonize the effects of Th1 cells. Tr1 cells, a recently described subset of Th cells, resemble Th2 cells by producing IL-5 and -10 but also produce IFN-gamma similar to Th1 cells. Importantly, Tr1 cells are present in the digestive tract and attenuate the host response to luminal antigen including the induction of colitis in animal models. Cytokines associated with Tr1 cells prevent the generation of ROS, the expression of genes associated with Th1 cells and their effects on bacterial binding and epithelial cell damage. These observations suggest that a "protective" response to vaccines will induce Tr1 cells, or related regulatory Th cells, that are responsible for limiting inflammation. How these cells are derived is unknown and their role in host defense has yet to be defined. This background leads to our general hypothesis that a relative imbalance in helper T cell subsets favors the stimulation of inflammation and epithelial damage in response to persistent infection with H. pylori. More specifically, oxidative stress associated with H. pylori infection selects for "pathogenic" Th1 responses that contribute to epithelial damage while a regulatory "protective" Th1 cell will favor tissue integrity and immunity. The overall objective is to define the T cell response to natural infection with H. pylori or immunization and elucidate the mechanisms governing lymphoepithelial cell interactions in disease versus immunity. This will be achieved in the following Specific Aims: 1). Define the factors selecting for "pathogenic" Th cells associated with H. pylori infection. 2). Identify T cell markers that are correlates of immunity. 3). Define mechanisms of host defense attributed to "protective" Th cells.